nci ngs meeting may ?, 2012 so now what do we do?: ngs in clinical laboratories stan hamilton, md...
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NCI NGS MeetingMay ?, 2012
So Now What Do We Do?:NGS in Clinical Laboratories
Stan Hamilton, MD
Professor and Head
Pathology and Laboratory Medicine
SPECIMENS
IACS
IPCT
THORACIC LAB
OTHERS
MOLECULARPATHOLOGY
MTMTF
MTEC
RESEARCHPre-CLIAdevelopment
CLIA Labs(CAP-accredited)
Cell blocks
Biopsyspecimens
Biopsyspecimens
Surgicalspecimens
OR Suites
Tissue Qualification
Lab
OutpatientClinics
Outside Facilities
CytologyLab
ExpeditorOffice
CLINICAL
MolecularDiagnostics
Lab
OtherP&LM
ClinicalLabs
ASSAYS
PATIENTS
The ClinicalGenomics
Biorepository(TCGB)
RoutineHistology
Lab
Alkek G5 & Mays Clinic
FrozenSection Labs
IR, US & Endoscopy
Suites
FNAspecimens
Blocks &slides
Assay results
TISSUE MOLECULAR BIOMARKER CONTINUUM
Roles for clinical labs
• Address all phases of testing– Pre-analytical, analytical, post-
analytical
• Fulfill clinical needs (and wants)– Criteria
• Provide quality for patient safety• Maintain regulatory compliance• Achieve fiscal goals
Ordering physician/ designee submits
request using Order Set / ClinicStation
Expeditor office prints request and
patient history reports (most recent case)
Pathologist performs Initial
Review of available slides
and reports
Pathologist selects the block(s) that he/she wants to use for the case
Expeditor takes the case
paperwork and on-hand materials to the Pathologist
Expeditor takes the
material to the Histology Lab
Histology Lab cuts the material and returns materials to the Expeditor
The Expeditor progresses “R” case to “Slide Marking”, sorts cases by subspecialty and takes the cut material to
the Pathologist
Is the selected material
on-site ?
No
Expeditor requests the material from storage facility or
another facility
Materials are received by
Outside Slides area
Expeditors received
material from Outside Slides
The Expeditor progresses “R” case to “Materials to Lab” and places materials
in Courier Outbox
Sufficient tumor cells/slides for testing
No
Yes
Courier takes material to Labs
BioMarkers - Pathology Pre-Analytic Process FlowCurrent State as of Jan 2012
Expeditor collects any on-hand materials from slide room
Expeditor completes online Histology
Request and progresses “R” case to ”Materials sent to
Histology”
Pathologist reviews materials,
marks slides, circles tumor cells, H&E and identifies
% tumor cell
Does History Indicate that MDL may have source
materials on hand?
DNA Available
Slides Available
Slides Prepared
Storage facility or another facility sends materials
Leave case with
Pathologist
Wait while Pathologist
marks slide(s)No
Yes
Pathologist requests additional materials
Yes
Ordering Physician
Histology Lab
Outside SlidesStorage/ facility
Surgical PathologistExpeditor
Courier
YesCharges needed
Issue PO
No
Yes
Submit Communication Form to CPAS & Home Center for
Financial Clearance
Expeditor progresses “R” case to “Additional Materials Requested” or “Warehouse Requested
Ready for MDL Lab to Process & Analyze
Accession “R” case in PowerPath;
progress case to “Material to Expeditors”
The Expeditor progresses “R”
case to “Materials to
MDL”
Ask MDL if enough DNA is
on hand
No (95+%)
Enough Source
Material On-Hand?
Yes (<5%)Yes
No
Powerpath/ ClinicStation Tracking Updates
NoCancel
Support Svcs. Mgr.
New roles for the pathologist
• Assay selection and development
• Clinical therapeutics consultation
• Specimen acquisition and qualification
• Assay quality control/quality assurance
• Assay results interpretation
• Regulatory and fiscal environment
• Competitive environment
Deciding on what’s ready for clinical use
NGS strategies
• Whole genome sequencing (WGS)– Somatic mutations in tumor– Germline mutations and
polymorphisms
• Whole exome sequencing (WXS)• Sequencing of targets for
actionable alterations (ACGS)• Informatics support
NGS strategies for clinical labs
• The driver: Clinical utilization of sequence data– The problem of reporting complex results
in clinically understandable format– “Umbrella” trials of new targeted agents– Novel usage of existing agents to target
pathways– Novel combinations of agents– Validated and actionable data
NGS beyond nucleotide substitutions
• Small insertions and deletions (indels)
• Copy number variations– Amplifications– Losses
• Chromosomal re-arrangements
• Methylation
• Gene expression
• Functional genomics
Evaluation of evidence
• Levels– Green and Byar, 1984
– TMUGS, 1996
– Lassere et al., 2007
– NCCN Task Force, 2011
• Depth
• Breadth
Levels of evidence: NCCN Task Force
TMUGS level Archived tissue level Validation studies
I A Not required
I B > 0, consistent
II B 0 or inconsistent
II C > 1, consistent
III C 0 or 1, consistent or inconsistent
IV-V D N/A
New roles for the pathologist
• Assay selection and development
• Clinical therapeutics consultation
• Specimen acquisition and qualification
• Assay quality control/quality assurance
• Assay results interpretation
• Regulatory and fiscal environment
• Competitive environment
Clinical therapeutics consultation
Drugs for a patient,
or patients for drugs.
Manuel Hidalgo, MD
Clinical care or clinical trial
New roles for the pathologist
• Assay selection and development
• Clinical therapeutics consultation
• Specimen acquisition and qualification
• Assay quality control/quality assurance
• Assay results interpretation
• Regulatory and fiscal environment
• Competitive environment
Updated November 2011
Quality of specimens
• Labile analytes– mRNA– Proteins– Phosphoproteins
• Smaller samples
• Real-time non-destructive qualification (e.g. optical confluence tomography)
Quality of specimens
• Fit-for-purpose selection of sources– Primary tumor– Metastatic tumor– Non-neoplastic control tissue for specific
assays: peripheral blood leukocytes or tissue
– Elapsed time between specimen and test– Potential effects of prior therapy– Circulating tumor cells
New roles for the pathologist
Intratumoral heterogeneity
N Engl J Med 2012
Tumor heterogeneity
• Importance for analytes of interest: Comparison of primary CRC to metastasis and comparison among metastases– KRAS: Relatively concordant (90%)– NRAS: Highly discordant
• Loss from primary• Acquisition in metastasis
• Size of abnormal subpopulations
New roles for the pathologist
• Assay selection and development
• Clinical therapeutics consultation
• Specimen acquisition and qualification
• Assay quality control/quality assurance
• Assay results interpretation
• Regulatory and fiscal environment
• Competitive environment
Circ Cardiovasc Genet, 2010
New roles for the pathologist
• Assay selection and development
• Clinical therapeutics consultation
• Specimen acquisition and qualification
• Assay quality control/quality assurance
• Assay results interpretation
• Regulatory and fiscal environment
• Competitive environment
The regulatory environment
• CLIA vs. FDA– Laboratory-developed tests (LDTs)– Complex assays
• FDA– Companion diagnostics
• NCI Cancer Diagnostics Program (CDP)• Professional organizations: ASCO,
NCCN, CAP, ASCP, AMP, IOM, etc., etc.• Gene patents
The fiscal environment
The $1,000 genome,
the $100,000 analysis.
Elaine Mardis, PhD
Washington University,
St. Louis
The fiscal environment
• Who wants to pay?
• Who pays?
• Who gets to decide?
The fiscal environment
• Who wants to pay?– Nobody
• Who pays?
• Who gets to decide?
Molecular Testing Evaluation Committee (MTEC)
SPECIMENS
TISSUE MOLECULAR BIOMARKER CONTINUUM
IACS
IPCT
THORACIC LAB
OTHERS
MOLECULARPATHOLOGY
MTMTF
MTEC
RESEARCHPre-CLIAdevelopment
CLIA Labs(CAP-accredited)
Cell blocks
Biopsyspecimens
Biopsyspecimens
Surgicalspecimens
OR Suites
Tissue Qualification
Lab
OutpatientClinics
Outside Facilities
CytologyLab
ExpeditorOffice
CLINICAL
MolecularDiagnostics
Lab
OtherP&LM
ClinicalLabs
ASSAYS
PATIENTS
The ClinicalGenomics
Biorepository(TCGB)
RoutineHistology
Lab
Alkek G5 & Mays Clinic
FrozenSection Labs
IR, US & Endoscopy
Suites
FNAspecimens
Blocks &slides
Assay results
MTEC roster and governance
• Multidisciplinary clinical Division Heads, Department Chairs, and faculty
• Administrative personnel: Clinical activities, patient services, compliance, billing, and clinical research
• Patient data acquisition and analysis• Patient advocacy• Subcommittee of the Executive Committee
of the Medical Staff and reports to the Medical Practice Committee
Charge to the MTEC
• Standard of care• Routine clinical ordering • EMR order entry sets• Investment of institutional funds• Documentation for negotiations with third-
party and second-party payers• Advanced Beneficiary Notification (ABN) • Documentation of medical necessity,
billing compliance, and utilization
New roles for the pathologist
• Assay selection and development
• Clinical therapeutics consultation
• Specimen acquisition and qualification
• Assay quality control/quality assurance
• Assay results interpretation
• Regulatory and fiscal environment
• Competitive environment
Competition for reimbursement
• Hospital labs• Reference labs: Megalabs, niche labs• Diagnostic assay companies• Benefits management companies• Direct-to-consumer or -physician companies• Advisory and educational service companies• Non-pathologist professionals• Accountable Care Organizations
Summary
• Current great emphasis on NGS biomarkers
• Need for information- and intelligence-driven decisions
• Complex processes
• Need for regulatory compliance
• Stringency of approach for quality
Thanks for your attention.